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Tumor radiation resistance is the main obstacle to effective radiotherapy of hepatocellular carcinoma (HCC) patients. we identified the role of urea cycle key enzyme carbamoyl phosphate synthetase 1 (CPS1) in radioresistance of HCC and explored its mechanism, aiming to provide a novel radiosensitization strategy for the CPS1-deficiency HCC subtype.The expression of CPS1 was measured by western blot and immunohistochemistry; Cell growth assay, EdU assay, cell apoptosis assay, cell cycle assay, clone formation assay, and subcutaneous tumor assay were performed to explore the relationship between CPS1 and radioresistance of HCC cells; lipid metabonomic analysis was used for investigating the effects of CPS1 on lipid synthesis of HCC cells; RNA-sequencing and co-immunoprecipitation assay were carried out to reveal the mechanism of CPS1 participating in the regulation of HCC radiotherapy resistance; Furthermore, 10074-G5, the specific inhibitor of c-Myc, was administered to HCC cells for investigating the role of c-Myc in CPS1-deficiency HCC cells.We found that urea cycle key enzyme CPS1 was frequently lower in human HCC samples and positively associated with the patient's prognosis. Functionally, the present study proved that CPS1 depletion could accelerate the development of HCC and induce radiation resistance of HCC in vitro and in vivo, and deficiency of CPS1 promoted the synthesis of some lipid molecules. Mechanismly, we uncovered that inhibition of CPS1 upregulated CyclinA2 and CyclinD1 by stabilizing oncoprotein c-Myc at the post-transcriptional level and generated radioresistance of HCC cells. Moreover, inactivation of c-Myc using 10074-G5, a specific c-Myc inhibitor, could partially attenuate the proliferation and radioresistance induced by depletion of CPS1.Our results recapitulated that silencing CPS1 could promote HCC progression and radioresistance via c-Myc stability mediated by the ubiquitin-proteasome system, suggesting that targeting c-Myc in CPS1-deficiency HCC subtype may be a valuable radiosensitization strategy in the treatment of HCC.

Background: Clinical trials demonstrated that immune checkpoint inhibitors (ICIs) combined with antiangiogenic drugs had achieved promising outcomes in the third-line and further treatment in metastatic colorectal cancer (mCRC) patients (pts) with microsatellite-stable (MSS) or proficient mismatch repair. Radiotherapy (RT) may enhance the anti-tumor effect of immunotherapy. However, the outcomes of RT on pts receiving targeted therapy plus ICIs remains unclear. Therefore, this study was aimed to investigate the association between RT exposure and clinical responses to fruquintinib plus sintilimab (F&S) in previously treated MSS-CRC and explore predictive biomarkers. Methods: This prospective observational cohort study assessed treatment outcomes of F&S as the third- or further-line therapy for advanced CRC pts at Wuhan Union Hospital from Mar 2021 to Jun 2022 (NCT05635149). The pts were divided into two cohorts according to their RT history. The objective response rate (ORR) was set as the primary endpoint. We collected pre-treatment stool samples from pts for microbiota sequencing. Results: A total of 55 pts were enrolled, of whom 25 pts received prior RT (RT cohort, RTC) and the other 30 pts had no exposure to RT (non-RT cohort, NRTC). Globally, the objective response rate (ORR) was 18.0%, the DCR was 56.3%, and the median PFS (mPFS) was 3.6 mo. When compared between the two cohorts, the ORR was 28.0% vs. 6.7% (OR=7.344, P=0.039, RTC vs. NRTC, the same hereinafter), the DCR was 80.0% vs. 36.7% (OR=7.991, P=0.010), and the mPFS was 6.1 mo vs. 2.6 mo (HR=0.286, P Conclusion: In this study, we found that pts with RT exposure could benefit more from F&S as the third- or further-line therapy in MSS colorectal cancer. Furthermore, bifidobacteria and lactobacillus enriched in baseline stool samples from pts in RTC, which may be potential biomarkers for outcomes. Further studies with larger scale sample size are warranted to validate our findings. Citation Format: Min Jin, Mingxia Cheng, Shengli Yang, Lei Zhao, Dandan Yu, Zhenyu Lin, Pindong Li, Jing Wang, Jun Xue, Hong Ma, Jianli Hu, Tao Zhang, Hongli Liu. Radiotherapy exposure and baseline gut microbiota predict clinical outcomes of fruquintinib plus sintilimab in microsatellite-stable metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB302.

Metabolic reprogramming is a feature of cancer cells and crucial for tumor growth and metastasis. Interferon-γ (IFNγ) is a cytokine that plays a pivotal role in host antitumor immunity. However, little is known about the roles of metabolic reprogramming in immune responses. Here, we show that colon cancer cells reprogram metabolism to coordinate proper cellular responses to IFNγ by downregulating mitochondrial pyruvate carrier (MPC)1 and 2 via STAT3 signaling. Forced overexpression of MPC promote the production of reactive oxygen species and enhance the apoptosis induced by IFNγ in colon cancer cells. Moreover, inhibiting STAT3 sensitize the antitumor efficacy of IFN-γ against colon cancer cells. Our findings present a previously unrecognized mechanism that colon cancer manipulate to resist IFNγ mediated antitumor immunity that have implications for targeting a unique aspect of this disease., Graphical abstract fx1, Highlights • IFNγ induces MPC downregulation via stat3 activation. • MPC promote the production of ROS and enhance the apoptosis. • STAT3 inhibition sensitize the antitumor efficacy of IFN-γ.

Accumulating evidence have suggested that long noncoding RNAs (lncRNAs) are known to regulate diverse tumorigenic processes. Recently, a novel lncRNA LINC01939 was underexpressed and emerged as a tumor suppressive lncRNA in gastric cancer (GC). In this study, we aimed to investigate the biological function and molecular mechanism of LINC01939 in GC. We found that LINC01939 expression was significantly downregulated in GC tissues and cell lines. Low expression of LINC01939 was correlated with tumor metastasis and shorter survival in GC patients. Functionally, LINC01939 overexpression remarkably inhibited the invasion and migration of GC cells in vitro and in vivo. Mechanistically, LINC01939 regulated the expression of early growth response 2 (EGR2) protein by competitively binding to miR-17-5p. Upregulation of miR-17-5p reversed GC metastasis and EMT process caused by LINC01939 by rescue analysis. Taken together, these results suggested that LINC01939 repressed GC invasion and migration by functioning as a ceRNA for miR-17-5p to regulate EGR2 expression. Our findings provided a novel prognostic marker and therapeutic target for GC patients.

e16227 Background: Neoadjuvant therapy has been attempted to improve local control and prolong survival for pancreatic cancer patients. However, the standard treatment has not been defined. This trial was to evaluate the efficacy and safety of nab-paclitaxel/gemcitabine plus camrelizumab with or without stereotactic body radiation therapy (SBRT) in patients with resectable, borderline-resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC). Methods: This prospective clinical trial was designed to include patients pathologically confirmed and previously untreated resectable pancreatic cancer, BRPC and LAPC. Patients were randomized to receive either SBRT (5 Gy × 5), four courses of nab-paclitaxel 125 mg/m2, gemcitabine 1000 mg/m2 (administered intravenously on days 1, 8 of each 21-day cycle) plus Camrelizumab 200mg (every three weeks) followed by surgery (Arm A) or only four courses of nab-paclitaxel, gemcitabine and Camrelizumab followed by surgery (Arm B). The primary endpoint was objective response rate (ORR), and the second endpoints were disease control rate (DCR), margin-negative (R0) resection rate, progression-free survival (PFS), overall survival (OS) and toxicity. Results: From March 2021 to Jan 2022, 14 eligible patients were enrolled. Eight patients were randomly assigned to Arm A while 6 to Arm B. The median follow-up duration was 33 weeks. Overall, 9 patients completed preoperative therapy and were eligible for response assessment. Among the 9 patients, 4 (44.4%) had partial response (PR), 4 (44.4%) had stable disease (SD), while one had progressive disease (PD). The ORR was 44.4% (4/9), and DCR was 88.9% (8/9). Five of these 9 patients received pancreatectomy with a resection rate of 71.4% (5/7) and the R0 resection rate was 100% (5/5). The reasons why the other 4 patients did not undergo surgery were progression of disease (n = 1), refusal of surgery (n = 1), and still in the interval of neoadjuvant therapy to surgery (n = 2). The most common adverse events of grade 3 or higher were neutropenia (22.2%), neuropathy (11.1%) and thrombocytopenia (11.1%). Median CA 19-9 level was 116U/ml (2 to 12000) in baseline while decreased to 69U/ml (2 to 4832) before surgery. The median OS or PFS has not been reached yet. Conclusions: The neoadjuvant therapy of nab-paclitaxel/gemcitabine plus camrelizumab with or without SBRT had a good safety and efficacy in patients with resectable pancreatic cancer, BRPC and LAPC. Clinical trial information: ChiCTR2100042415. [Table: see text]

Calcium activated Chloride Channel A4 (CLCA4), as a tumor suppressor, was reported to contribute to the progression of several malignant tumors, yet little is known about the significance of CLCA4 in invasion and prognosis of hepatocellular carcinoma (HCC). CLCA4 expression was negatively correlated with tumor size, vascular invasion and TNM stage. Kaplan-Meier analysis showed that CLCA4 was an independent predictor for overall survival (OS) and time to recurrence (TTR). In addition, CLCA4 status could act as prognostic predictor in different risk of subgroups. Moreover, combination of CLCA4 and serum AFP could be a potential predictor for survival in HCC patients. Furthermore, CLCA4 may inhibit cell migration and invasion by suppressing epithelial-mesenchymal transition (EMT) via PI3K/ATK signaling. Knockdown of CLCA4 significantly increased the migration and invasion of HCC cells and changed the expression pattern of EMT markers and PI3K/AKT phosphorylation. An opposite expression pattern of EMT markers and PI3K/AKT phosphorylation was observed in CLCA4-transfected cells. Additionally, immunohistochemistry and RT-PCR results further confirmed this correlation. Taken together, CLCA4 contributes to migration and invasion by suppressing EMT via PI3K/ATK signaling and predicts favourable prognosis of HCC. CLCA4/AFP expression may help to distinguish different risks of HCC patients after hepatectomy.

Thyroid cancer is the most common endocrine carcinoma with increasing incidence worldwide and anaplastic subtypes are frequently associated with cancer related death. Radioresistance of thyroid cancer often leads to therapy failure and cancer-related death. In this study, we found that melatonin showed potent suppressive roles on NF-κB signaling via inhibition of p65 phosphorylation and generated redox stress in thyroid cancer including the anaplastic subtypes. Our data showed that melatonin significantly decreased cell viability, suppressed cell migration and induced apoptosis in thyroid cancer cell lines in vitro and impaired tumor growth in the subcutaneous mouse model in vivo. By contrast, irradiation of thyroid cancer cells resulted in elevated level of phosphorylated p65, which could be reversed by cotreatment with melatonin. Consequently, melatonin synergized with irradiation to induce cytotoxicity to thyroid cancer, especially in the undifferentiated subgroups. Taken together, our results suggest that melatonin may exert anti-tumor activities against thyroid carcinoma by inhibition of p65 phosphorylation and induction of reactive oxygen species. Radio-sensitization by melatonin may have clinical benefits in thyroid cancer. Keywords: Melatonin, Thyroid cancer, Radioresistance, p65, Reactive oxygen species

Nanotechnology provides a novel scope for cancer therapeutics. Nanoscale platforms could influence the survival, adhesion, and migration of cancer cells through altering the tumor microenvironments. We report here the development of an anti-tumor material designed specifically for cancer therapy. We synthesized a 48-amino acid peptide RADA-KLA, which could self-assemble into nanostructures with antitumor activities. We tested the microstructure of RADA-KLA nanofiber scaffold using transmission electron microscopy (TEM) and accessed rheological properties of the material. Then, we demonstrated the effects of RADA-KLA nanofibers on hepatoma carcinoma cells. We found that RADA-KLA self-assembling peptide scaffold could induce cell death, and inhibit adhesion and migration of hepatoma carcinoma cells. Our results indicate that the designer peptide scaffold has anti-tumor activities and could be used for cancer therapy. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2329-2334, 2017.

BackgroundInterferon-α (IFN-α) plays a pivotal role in host antitumor immunity, and the evasion of IFN-α signaling pathway can lead to IFN-α resistance during the treatment of cancer. Although the interplay between IFN-α and tumor cells has been extensively investigated in differentiated tumor cells, much less attention has been directed to tumor-repopulating cells (TRCs).MethodsThree-dimentional soft fibrin matrix was used to select and grow highly malignant and tumorigenic melanoma TRCs. The regulation of integrin β3 (ITGB3)-c-SRC-STAT signaling pathway in melanoma TRCs was investigated both in vitro and in vivo. The relevant mRNA and protein expression levels were analyzed by qRT-PCR and western blot analysis. Immunoprecipitation and chromatin immunoprecipitation (ChIP) followed by qPCR (ChIP-qPCR) assays were performed to detect protein-protein and protein-DNA interactions. The clinical impacts of retinoic acid inducible gene-I (RIG-I) were assessed in melanoma datasets obtained from The Cancer Genome Atlas and Gene Expression Omnibus profiles.ResultsIFN-α-induced apoptosis was decreased in melanoma TRCs. Compared with conventional flask-cultured cells, IFN-α-mediated STAT1 activation was diminished in melanoma TRCs. Decreased expression of RIG-I in melanoma TRCs led to diminished activation of STAT1 via enhancing the interaction between Src homology region 2 domain-containing phosphatase-1 and STAT1. In addition, low expression levels of RIG-I correlated with poor prognosis in patients with melanoma. STAT3 was highly phosphorylated in TRCs and knockdown of STAT3 reversed the downregulation of RIG-I in TRCs. Knockdown of STAT3 resulted in STAT1 activation and increased expression of the pro-apoptosis genes in IFN-α-treated TRCs. Combined treatment of STAT3 inhibitor and IFN-α increased the apoptosis rate of TRCs. Disruption of ITGB3/c-SRC/STAT3 signaling pathway significantly elevated the efficiency of IFN-α-induced apoptosis of TRCs.ConclusionsIn melanoma TRCs, ITGB3-c-SRC-STAT3 pathway caused RIG-I repression and then affect STAT1 activation to cause resistance to IFN-α-induced apoptosis. RIG-I is a prognostic marker in patients with melanoma. Combination of STAT3 inhibitor and IFN-α could enhance the efficacy of melanoma treatment. Our findings may provide a new concept of combinatorial treatment for future immunotherapy.

Inhibitor for the apoptosis-stimulating protein of p53 (iASPP) has been reported to be correlated with 5-fluorouracil (5-Fu) resistance in renal cell carcinoma. Here, we uncover mechanisms of iASPP-Nrf2-ROS regulation of 5-Fu resistance which are important for the development of alternative treatment strategies for gastric adenocarcinoma treatment. We analyzed iASPP and Nrf2 through TCGA RNA-seq data, UALCAN analysis, and cBioPortal datasets. Intracellular ROS generation was determined by 2′,7′-dichloro-fluorescin diacetate staining. Transwell was used to evaluate the invasion. The expression of iASPP, Nrf2, HO-1, and GSTP1 was tested using western blot. We found that iASPP KD led to an apparent 5-Fu-induced ROS accumulation in MGC803 and SCG790 cells. Accompanied by iASPP KD, Nrf2 was markedly decreased. iASPP-induced ROS inhibition relies on Nrf2, and due to both knocked down iASPP and Nrf2, the level of ROS did not show an obvious difference with Nrf2 KD solely. Similarly, iASPP KD failed to enhance the Nrf2 KD-mediated ROS accumulation after 5-Fu treatment, suggesting that iASPP-induced antioxidative effects related to 5-Fu resistance are partially dependent on Nrf2. Also, the combination of iASPP KD and Nrf2 KD did not show any synergistic effect on apoptosis after 5-Fu treatment in MGC803 and SCG790 cells. Further studies revealed that iASPP KD or Nrf2 KD could decrease the expression of HO-1 and GSTP1. Our data highlight that iASPP plays a crucial role in the inhibition of 5-Fu-induced apoptosis resistance by removing ROS accumulation in gastric adenocarcinoma, and that the removal of ROS induced by iASPP is Nrf2 signaling dependent.

Additional file 3: Table S1. Univariate analysis between gene mutations and PFS. Table S2. Univariate analysis between variants and PFS. Table S3. Univariate analysis between gene mutations and OS. Table S4. Univariate analysis between variants and OS.

The design of biocompatible and efficacious anticancer biomaterials to achieve relatively low tumor recurrence rates is the main pursuit of cancer photothermal therapy (PTT). RADA16-I is a synthetic amphiphilic peptide with the sequence RADARADARADARADA that can self-assemble into a peptide nanofiber hydrogel. In this study, we synthesized a novel melittin–RADA32–indocyanine green (ICG) hydrogel (“MRI hydrogel”), which contains melittin in the peptide hydrogel backbone and ICG in the hydrogel matrix, for enhanced PTT of glioblastomas. The MRI hydrogel exhibited physiologic characteristics similar to those of the RADA16 hydrogel, while displaying concentration-dependent cytotoxicity to C6 glioma cells and photothermal effects. The in vivo biodistribution of the MRI hydrogel was visualized by near-infrared fluorescence and photoacoustic imaging. More importantly, in vivo PTT provided by the MRI hydrogel significantly reduced the tumor size and the tumor recurrence rate compared with the RADR16-ICG hydrogel ...

KRAS mutations are prevalent in non-small cell lung cancer (NSCLC) but its clinical implications remain to be determined. Continual profiling of KRAS mutations in patients is challenging, and the study aims to determine the potential use of urinary DNA in disease predictions. A total of 150 patients were recruited. To ascertain the clinical relevance of urinary DNA, matched tumor profiles were analyzed. Serial measurements were taken to gauge the reliability of the assay. These results were correlated to overall survival using the Kaplan–Meier estimate. A good overall concordance of 93% (consolidated results from serial measurements) was achieved between tumor tissue and urinary DNA profiling. Of the discordant KRAS cases, we observed subsequent positive detection during monitoring and very low concentrations of mutant DNA. In addition, we noted that KRAS-positive patients detected using urinary DNA have good prognostic utility. Interestingly, we also observed that the trend is highly correlative of the rate of change in KRAS mutant DNA concentrations and the period of monitoring. Urinary DNA offered a non-invasive approach to probe NSCLC dynamics, and in our study we showed that it had predictive capabilities for KRAS-positive patients. Serial monitoring of urinary samples showed that it had a predictive role in identifying patients with worse outcome.

Background. Nasopharyngeal carcinoma (NPC) is a major cancer in southern China. Src homology phosphatase-1 (SHP-1) is a tyrosine phosphatase that regulates growth, differentiation, cell cycle progression, and oncogenesis. We determined the clinical significance of SHP-1 expression in the tumours of NPC patients from southern China who were treated with radiotherapy. Patients and methods. SHP-1 expression was determined by real-time polymerase chain reaction (PCR) and western blotting of NPC tissue samples of 50 patients and nasopharyngeal tissues of 50 non-NPC patients who had chronic nasopharyngeal inflammation. SHP-1 expression was measured in NPC tissue samples of 206 patients by immunohistochemistry and survival analysis was performed. Results. The tumours of NPC patients had significantly increased expression of SHP-1 at mRNA and protein levels relative to patients with chronic nasopharyngeal inflammation. Survival analysis of NPC patients indicated that SHP-1 expression was significantly associated with poor local recurrence-free survival (p = 0.008), but not with nodal recurrence- free survival, distant metastasis-free survival, or overall survival. Conclusions. SHP-1 appears to be associated with radiation resistance of NPC cells and can be considered as a candidate marker for prognosis and/or therapeutic target in patients with this type of cancer.

Peptide self-assembling scaffolds have been widely used in tissue engineering. Much work has been focused on modifying the self-assembling scaffolds with functional motifs for desired biological activities. We report here the development of a biological material designed specifically for neural tissue engineering (NTE). Using RADA-16 (AcN-RADARADARADARADA-CONH2) as a base scaffold, we synthesized a 31 amino acid peptide RADA-FRM (AcN-RADARADARADARADAGGSIDRVEPYSSTAQ-CONH2) containing the neural cell adhesion molecule (NCAM)-derived mimetic peptide FRM (SIDRVEPYSSTAQ), which could undergo self-assembly into a nanofiber scaffold. We tested the characterization of the nanofiber scaffold using atomic force microscopy (AFM) and accessed the rheological properties of FRM-containing nanofiber scaffold (FRM-NS). Then we examined its biocompatibility on neural stem cells (NSCs) from neonatal rats. Regrettably, we found that FRM-NS had no effect on differentiation of NSCs. However, we tested that FRM-NS was noncytotoxic. Furthermore, compared to pure RADA-16 scaffold, we found that the designer self-assembling peptide scaffold containing FRM motif could significantly promote NSCs proliferation and stimulate NSCs migration into the three-dimensional scaffold. Our results indicate that the novel designer peptide scaffold containing FRM had excellent biocompatibility with NSCs and may be useful for central nervous tissue repair.

Heme oxygenase-1 (HO-1) plays a key role in anti-oxidation, anti-apoptosis, and anti-proliferation in various types of cancers. However, the relationship between HO-1 expression and gastric cancer development remains largely unknown. In this study, the protein expression of HO-1 in human gastric cancer was measured by immunohistochemistry on paraffin sections of 89 paired gastric carcinoma tissues and adjacent non-cancer tissues. The correlation of HO-1 expression with 5-year overall survival rate was estimated. The effects of decreased HO-1 expression by two strands of small interfered RNAs (siRNAs) on cell apoptosis, proliferation, and invasion of gastric cancer cell lines were examined by flow cytometry, the MTT assay, and the cell migration assay, respectively. High expression of HO-1 was detected in 11.2% (10/89) of gastric carcinoma tissues, compared with 1.1% (1/89) in matched adjacent normal tissues, and correlated with a decreased survival rate in gastric cancer patients. There were no significant correlations between HO-1 expression and clinical characteristics. Downregulation of HO-1 expression using two strands of siRNAs promoted apoptosis and inhibited the proliferation and invasion of two gastric cancer cell lines, SGC7901 and MKN-28 cells. This study demonstrated that HO-1 plays a vital role in the development of gastric cancer and may serve as a therapeutic target of this type of cancer.

Nanotechnology provides a novel scope for cancer therapeutics. Nanoscale platforms could influence the survival, adhesion, and migration of cancer cells through altering the tumor microenvironments. We report here the development of an anti-tumor material designed specifically for cancer therapy. We synthesized a 48-amino acid peptide RADA-KLA, which could self-assemble into nanostructures with antitumor activities. We tested the microstructure of RADA-KLA nanofiber scaffold using transmission electron microscopy (TEM) and accessed rheological properties of the material. Then, we demonstrated the effects of RADA-KLA nanofibers on hepatoma carcinoma cells. We found that RADA-KLA self-assembling peptide scaffold could induce cell death, and inhibit adhesion and migration of hepatoma carcinoma cells. Our results indicate that the designer peptide scaffold has anti-tumor activities and could be used for cancer therapy. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2329-2334, 2017.

To characterize the expression patterns of HDAC7 in patients with gastric cancer and evaluate the prognostic value of HDAC7 in gastric cancer. The expression of histone deacetylase 7 (HDAC7) was detected in paraffin-embedded gastric cancer samples from 86 patients by immunohistochemistry, and the differences in the expression of HDAC7 between cancerous and corresponding adjacent noncancerous tissues were compared using the Wilcoxon matched-pairs signed rank test. The correlation between HDAC7 expression and Ki-67 expression or clinicopathologic characteristics was evaluated using a Spearman rank correlation test. Prognostic outcomes that correlated with HDAC7 were examined using a Kaplan–Meier analysis and Cox proportional hazards model. Moreover, the effects of HDAC7 on the proliferation, migration and invasion of gastric cancer cells were investigated in vitro using human gastric carcinoma AGS cells. We found that HDAC7 was downregulated in cancerous gastric tissues (P = 0.0019). However, the expression of HDAC7 in cancerous gastric tissues positively correlated with Ki-67 expression (P = 0.0325) and distant metastasis (P = 0.020). Moreover, overall survival was shorter for patients expressing higher levels of HDAC7 in cancerous tissues (P = 0.042). Mechanistically, the disruption of the HDAC7 gene attenuated the capacity of cell growth, migration and invasion and induced G0/G1 arrest in AGS cells. Conversely, forced ovperexpression of HDAC7 promoted cell growth, migration and invasion and G1/S transition in AGS cells. These results indicate that high HDAC7 expression in cancerous gastric tissues correlates with distant metastasis and predicts a poor prognosis for patients with gastric cancer.

// Pin-Dong Li 1, 2, * , Jian-Li Hu 1, * , Charlie Ma 2 , Hong Ma 1 , Jing Yao 1 , Li-Li Chen 2 , Jing Chen 1 , Tian-Tian Cheng 3 , Kun-Yu Yang 1 , Gang Wu 1 , Wen-Jie Zhang 4 and Ru-Bo Cao 1 1 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China 2 Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA 3 Cancer Center of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510059, China 4 Department of Pathology, Shihezi University School of Medicine, Shihezi, Xinjiang 832002, China * These authors have contributed equally to this work Correspondence to: Ru-Bo Cao, email: caorubao@126.com Keywords: long non-coding RNA, PVT1, LASP1, miR-203, esophageal squamous cell carcinoma Received: November 01, 2016 Accepted: January 16, 2017 Published: March 03, 2017 ABSTRACT Long non-coding RNAs are a group of non-coding RNAs longer than 200 nucleotides and possess diverse functions and exhibit exquisite cell-specific and developmental dynamic expression patterns. The role of the long non-coding RNA PVT1 in esophageal squamous cell carcinoma remains unsolved. Here, we showed that PVT1 expression is significantly up-regulated in ESCC tumor samples compared with their normal counterparts. Knockdown of PVT1 suppressed tumor growth in vitro and in vivo . Further studies revealed that silence of PVT1 lead to up-regulation of miR-203, and vice versa. Moreover, LASP1 was found to be downregulated after knockdown of PVT1 and overexpression of LASP1 attenuated the tumor-suppressive roles of PVT1 knockdown. Our results suggest that PVT1 promote ESCC progression via functioning as a molecular sponge for miR-203 and LASP1 and provide the first evidence of dysregulated PVT1/miR-203/LASP1 axis in ESCC.

Patients with esophageal squamous cell carcinoma (ESCC) have a poor prognosis. However, the related mechanisms are unclear, thus we investigated the expression of HO-1 in ESCC tissue and explored possible mechanisms of tumor progression. Expression of HO-1 was examined by immunohistochemistry in 143 ESCC tumors. The correlation of HO-1 with clinicopathological characteristics was also examined. Two human ESCC cell lines, TE-13 and Eca109 were studied. Silencing of cell line HO-1 by specific small interfering RNA (siRNA) was evaluated using real-time quantitative PCR. Cell line viability, apoptosis and intracellular levels of reactive oxygen species (ROS) after transfection were determined using MTT and flow cytometry, respectively. HO-1, Bax, Bcl-2 and A-caspase-3/-9 expression was evaluated using western blot analyses. We found that HO-1 was expressed in 58 of 143 ESCC tumors, mainly in the cytoplasm. There was a significant association between HO-1 expression and tumor grade (P

Glutathione peroxidase 2 has important role of tumor progression in lots of carcinomas, yet little is known about the prognosis of glutathione peroxidase 2 in hepatocellular carcinoma. Glutathione peroxidase 2 expression was assessed by immunohistochemistry in hepatocellular carcinoma tissues. The association between glutathione peroxidase 2 expression with clinicopathological/prognostic value was examined. Glutathione peroxidase 2 overexpression was correlated with alpha-fetoprotein level, larger tumor, BCLC stage, and tumor recurrence. Kaplan–Meier analysis showed that glutathione peroxidase 2 was an independent predictor for overall survival and time to recurrence. glutathione peroxidase 2 overexpression was correlated with poor prognosis in patient subgroups stratified by tumor size, differentiation, tumor–node–metastasis, and BCLC stage. Moreover, stratified analysis showed that tumor–node–metastasis stage-I patients with high glutathione peroxidase 2 expression had poor prognosis than those with low glutathione peroxidase 2 expression. Additionally, combination of glutathione peroxidase 2 and serum alpha-fetoprotein was correlated with prognosis in hepatocellular carcinoma. In conclusion, glutathione peroxidase 2 overexpression contributes to poor prognosis of hepatocellular carcinoma patients and helps to identify the high-risk hepatocellular carcinoma patients.

Peptide self-assembling scaffolds have been widely used in tissue engineering. Much work has been focused on modifying the self-assembling scaffolds with functional motifs for desired biological activities. We report here the development of a biological material designed specifically for neural tissue engineering (NTE). Using RADA-16 (AcN-RADARADARADARADA-CONH2) as a base scaffold, we synthesized a 31 amino acid peptide RADA-FRM (AcN-RADARADARADARADAGGSIDRVEPYSSTAQ-CONH2) containing the neural cell adhesion molecule (NCAM)-derived mimetic peptide FRM (SIDRVEPYSSTAQ), which could undergo self-assembly into a nanofiber scaffold. We tested the characterization of the nanofiber scaffold using atomic force microscopy (AFM) and accessed the rheological properties of FRM-containing nanofiber scaffold (FRM-NS). Then we examined its biocompatibility on neural stem cells (NSCs) from neonatal rats. Regrettably, we found that FRM-NS had no effect on differentiation of NSCs. However, we tested that FRM-NS was noncytotoxic. Furthermore, compared to pure RADA-16 scaffold, we found that the designer self-assembling peptide scaffold containing FRM motif could significantly promote NSCs proliferation and stimulate NSCs migration into the three-dimensional scaffold. Our results indicate that the novel designer peptide scaffold containing FRM had excellent biocompatibility with NSCs and may be useful for central nervous tissue repair.

Background Radioresistance is the common cause for radiotherapy failure in non-small cell lung cancer (NSCLC), and the degree of radiosensitivity of tumor cells is different during different cell cycle phases. The objective of the present study was to investigate the effects of cell cycle redistribution in the establishment of radioresistance in NSCLC, as well as the signaling pathway of SH2 containing Tyrosine Phosphatase (SHP1). Methods A NSCLC subtype cell line, radioresistant A549 (A549S1), was induced by high-dose hypofractionated ionizing radiations. Radiosensitivity-related parameters, cell cycle distribution and expression of cell cycle-related proteins and SHP1 were investigated. siRNA was designed to down-regulate SHP1expression. Results Compared with native A549 cells, the proportion of cells in the S phase was increased, and cells in the G0/G1 phase were consequently decreased, however, the proportion of cells in the G2/M phase did not change in A549S1 cells. Moreover, the expression of SHP1, CDK4 and CylinD1 were significantly increased, while p16 was significantly down-regulated in A549S1 cells compared with native A549 cells. Furthermore, inhibition of SHP1 by siRNA increased the radiosensitivity of A549S1 cells, induced a G0/G1 phase arrest, down-regulated CDK4 and CylinD1expressions, and up-regulated p16 expression. Conclusions SHP1 decreases the radiosensitivity of NSCLC cells through affecting cell cycle distribution. This finding could unravel the molecular mechanism involved in NSCLC radioresistance.